NSAIDs: Pain Relief or Pain in the Gut?

The demands of athletic activity can (and often do) take their toll on the horse's body, particularly the joints, ligaments, tendons, bones, and muscles. Sole bruising, tendon strains, sprained suspensory ligaments, arthritic joints, and sore backs, to name but a few, are common injuries in athletic horses.

A process common to all of these ailments is inflammation--we are all very familiar with the "cardinal signs" of inflammation. The affected area is hot, swollen, and painful (the horse flinches when pressure is applied). For injuries involving the musculoskeletal system, there will be varying degrees of lameness, reflecting pain and loss of function of the affected tissues.

The most popular medications used in these situations are the non-steroidal anti-inflammatory drugs, also known by the acronym NSAIDs. The NSAIDs most commonly used in horses include phenylbutazone ("Bute"), meclofenamic acid (Arquel), flunixin meglumine (Banamine), ketoprofen (Ketofen), and aspirin. All except aspirin have received approval from the Food and Drug Administration (FDA) for use in horses. Naproxen has also been extensively used in horses, but an equine formulation is no longer available.

Most of us have used these drugs in our horses at one time or another and have some appreciation of their benefits. And there is no doubt that many of the NSAIDs are invaluable in the treatment of many of the ailments that can plague the athletic horse. However, some can be toxic, and you need to be aware of those risks.

In this article, we will review how these drugs work, look at what is known about the relative effectiveness and safety of the various NSAIDs used in horses, and review guidelines for the safe use of NSAIDs.

Dampening Inflammation and Pain

Inflammation is the body's natural response to injury. It also is a critical first step in the healing process. When the body's cells are injured, they release a number of chemical substances--including prostaglandins--that trigger an inflammatory response. These newly released prostaglandins increase blood flow to the damaged tissue, make blood vessels more "leaky," and produce pain in inflamed tissue. This step is key to understanding how NSAIDs work to combat inflammation and pain.

These drugs bind to an enzyme called cyclooxygenase (abbreviated COX) that directs production of the prostaglandins. So, once the drug has gained access to the inflamed area and ties up COX, there will be a decrease in the manufacture of prostaglandins and the inflammatory response will begin to subside (see "How NSAIDs Work" at right).

The pain-killing (analgesic) effect of NSAIDs is also mostly due to this decrease in prostaglandin production. When present in large amounts, prostaglandins "fire up" the nerves responsible for pain sensation. For this reason, you won't see immediate pain relief following administration of an NSAID because these drugs will have no effect on the prostaglandins already formed before drug administration. Fortunately, prostaglandins are short-lived in the body, and the benefits of an NSAID can be seen within a few hours.

Some NSAIDs have a more direct effect on pain, meaning they work on the central nervous system to deaden pain sensation very similar to the way in which a drug like morphine controls pain. This might be one reason why flunixin meglumine (Banamine) provides faster and more effective pain relief than some other NSAIDs.

In horses with colic (gastrointestinal) pain, flunixin (Banamine) can provide relief within 15 to 30 minutes. At the other end of the spectrum, it can take two to three days before the maximum benefits of meclofenamic acid (Arquel) are realized.

In general, most NSAIDs "kick in" after two to four hours, with peak effects after six to nine hours, and a decline after 12 hours. This explains why it is often necessary to give an NSAID twice daily to maintain anti-inflammatory effects and pain relief. However, there is considerable variation between drugs when it comes to speed and duration of anti-inflammatory effects.

Also consider how the drug is given. When an NSAID (mostly Bute or Arquel) is given by mouth, it first must be absorbed into the bloodstream, and then distributed throughout the body, so there will be some delay before the drug starts to take effect. In general, NSAIDs will work faster when given by injection (into a vein or muscle), although giving the drug by mouth is much more convenient when it needs to be given for a number of days. By and large, NSAIDs are well absorbed through the horse's gut, but the process can be slowed by feeding because some of the drug adheres to feed particles and is thus not absorbed into the horse's bloodstream. Also, feeding (especially higher fat diets) might slow stomach emptying, which lengthens the time the medication stays in the stomach and slows absorption. For these reasons, it is better to give the drug an hour or two before or after feeding.

Deciding What To Use

Many different opinions exist regarding the relative effectiveness of the NSAIDs used in horses. Extensive clinical experience and the results of several comparative studies have shown that some of the NSAIDs are best suited for certain problems. The best example is Banamine for a horse with colic.

Phenylbutazone is perhaps the most versatile of the NSAIDs approved for use in horses. It is economical, available in both injectable and oral formulations (the latter including powder, paste, gel, and tablet forms), and works well for a variety of common musculoskeletal disorders. However, as discussed below, Bute is also the drug most likely to cause problems if given too long (or at inappropriately high doses).

Aspirin has very weak anti-inflammatory and analgesic activity in horses and is not recommended for the treatment of musculoskeletal problems. On the other hand, meclofenamic acid, flunixin meglumine, and ketoprofen are all very effective in dealing with musculoskeletal ailments. The pain relief from flunixin and ketoprofen is longer-lasting than would be predicted by blood concentrations of the drug (and longer than an equivalent dose of Bute) because of drug accumulation at the site of inflammation.

Note that the beneficial effects of meclofenamic acid (Arquel) are relatively slow to develop (two to three days for maximum effect). This drug is most useful in managing chronic, low-grade problems such as navicular disease and bone spavin.

For those of you competing in events that are sanctioned by USA Equestrian, you must be fully conversant with the rules governing the use of NSAIDs (found at www.ahsa.org). These rules list the NSAIDs that can be used (phenylbutazone, flunixin, ketoprofen, meclofenamic acid, and naproxen), the maximum doses and duration of treatment allowed, and regulations governing the timing of administration before an event (usually no later than 12 hours prior to competing). Also, no more than two NSAIDs can be given at one time.

The 12-hour restriction means that the horse can compete with at least some anti-inflammatory and pain relief, but not enough to mask significant musculoskeletal problems. Remember, the goals of NSAID therapy are to control inflammation and pain and hasten recovery from injury, not to hide signs of serious injuries that probably need medical or surgical treatment (and certainly rest).

First and foremost, you should always call your veterinarian and allow him or her to diagnose any lameness problem before the horse is started on NSAID treatment.

Potential Problems

For the most part, use of NSAIDs in horses is a safe practice--however, it is possible to get too much of a good thing. When high doses are given for a lengthy period, there is a risk of problems. Rather than always being the "bad guys," the prostaglandins that NSAIDs inhibit are involved in a number of important body functions. These include protection of the cells that line the gastrointestinal tract, promotion of blood clotting, normal bone remodeling and repair, and maintenance of blood flow to the kidneys (particularly when the horse is a little dehydrated).

By decreasing prostaglandin production, NSAIDs can cause these processes to go awry. In the horse, gastrointestinal problems associated with NSAID use are the most common side effects, although there can also be problems with kidney function. Gastric irritation caused by NSAIDs (especially aspirin) is a big problem in humans. In fact, we seem to be more susceptible than horses when it comes to this side effect.

Gastrointestinal inflammation and ulceration--mostly involving the stomach and colon--are the main problems recognized in horses. NSAID toxicity in horses might cause them to exhibit a dull attitude, teeth grinding (often a sign of gut pain), mild colic signs, fever, and diarrhea. All of these signs are a reflection of the irritation and damage caused by the inhibition of prostaglandin synthesis in the gastrointestinal tract. Ulcers can also form in the mouth. Damage to the gastrointestinal tract results in a loss of body proteins, and in some cases, this loss of protein is severe enough to result in fluid accumulation along the under belly (edema).

Anti-ulcer medication (e.g. omeprazole, ranitidine, cimetidine) can be used in horses which have to be on NSAIDs long term due to musculoskeletal problems. These drugs might help prevent ulcers from occurring in the stomach (but not in the colon). Your veterinarian might recommend use of these drugs when long-term NSAID use is warranted.

Diagnosis of NSAID toxicity is not always easy because the clinical signs are fairly non-specific and can easily be mistaken for other gastrointestinal diseases such as Potomac horse fever and salmonellosis. However, a history of high-dose NSAID use over a period of weeks and the presence of mouth ulcers will raise suspicion.

Studies that have compared the toxic effects of some of the NSAIDs used in horses have shown that phenylbutazone is the most harmful, while flunixin and ketoprofen are less likely to result in problems. Young horses (foals and yearlings) seem to be more susceptible to the toxic effects of phenylbutazone. However, when it comes to gastrointestinal damage, the dose and duration of treatment are the most important risk factors--all NSAIDs are potentially harmful if given at inappropriately high doses for a lengthy period.

The bad news is that the prognosis for horses with NSAID toxicity is poor. The old saying "an ounce of prevention is worth a pound of cure" rings true when using these medications. The general rules for using NSAIDs are to:

Use these drugs under the guidance of your veterinarian;

Use the lowest possible dose (enough to achieve the desired effects) and calculate the dose based on the horse's actual body weight (estimates obtained using a weight tape are fine);

Keep the course of treatment as short as possible; and,

Monitor the horse very closely during the course of treatment.

Let's take phenylbutazone as an example. For a horse weighing 1,000-1,100 pounds (450-500 kg), the recommended dose is two to four grams per day, with this dose typically divided into morning and evening treatments. However, research studies have shown that a dose of four grams per day over a 10- to 14-day period can result in gastrointestinal toxicity. For this reason, most vets are very uncomfortable administering four grams of Bute per day for more than four or five days. For acute injuries (e.g., a tendon sprain or a tying-up episode), this high dose might only be used for a couple of days, and then cut back to two grams per day or less. The total course of treatment should be no more than 10 days.

Problems are more likely when treating a horse for severe and chronic injuries (e.g., tendon bows or osteoarthritis). Here, a longer course of treatment is often indicated, but you should not exceed a dose of two grams per day. The same general rule applies when using flunixin, meclofenamic acid, or ketoprofen. The manufacturer's maximum daily dose should not be exceeded.

Another scenario that increases the chances of a toxicity problem is giving two different NSAIDs at the same time (e.g., two grams of Bute and 10 ccs of Banamine) and continuing this treatment over a one- to two-week period. In essence, this is the same as giving four grams of Bute per day because the toxic effects of these drugs are additive. It is far safer to stick with only one NSAID.

The Future of Painkillers

Driven by the high prevalence of NSAID-induced gastric irritation in human patients, the pharmaceutical industry has worked hard to develop new drugs that carry a much lower risk of toxic side effects. We now know that there are at least two forms of the COX enzyme: COX-1 and COX-2. COX-1, which is present in most body tissues, maintains a steady production of the "good-guy" prostaglandins that the body needs. COX-2, on the other hand, only springs to action when there is tissue injury or other insults to the body such as bacterial and viral infections. Once activated, COX-2 produces huge quantities of prostaglandins that trigger many of the signs of inflammation.

Drugs such as phenylbutazone and flunixin block both COX-1 and COX-2, which is why use of these NSAIDs carries a risk of toxicity. New drugs on the human market for treatment of musculoskeletal pain and inflammation, such as celecoxib (Celebrex) and rofecoxib (Vioxx) are highly selective for inhibition of COX-2 and are therefore very effective anti-inflammatory agents. On the other hand, these drugs have minimal effects on prostaglandin production by COX-1, so the risk of side effects is greatly reduced.

A word of caution here, though--the safety and effectiveness of Celebrex and Vioxx in horses is not known. For this reason, these drugs should not be used in horses under any circumstances until more information on their use in horses is available.

Drugs that work more on COX-2 than COX-1 are available for use in dogs, and these newer-generation NSAIDs will eventually enter the equine market. Until then, you need to exercise some caution when giving your horses NSAIDs, and especially adhere to the instructions given by your veterinarian.

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